The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development.
The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development.
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DOI：
10.1371/journal.pone.0166703
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zaret KS
中科院分区：
文献类型：
--
作者：
Bhat N;Park J;Zoghbi HY;Arthur JS;Zaret KS
I型糖尿病是由分泌胰岛素的β细胞丧失引起的。为了确定新的、药理上有靶向性的组蛋白修饰蛋白，以促进胰岛前体细胞产生β细胞，我们对关键胰腺基因的信号转导通路诱导的组蛋白修饰进行了筛选。这一筛选使我们研究了Ser-28磷酸化组蛋白H3(H3S28ph)及其上游激酶MSK1和MSK2(MSK1/2)的时间动力学。H3S28ph和MSK1/2在E12.5多能胰腺祖细胞的关键内分泌启动子和腺泡启动子上富含。胚胎胰腺外植体中MSK1/2的药理抑制促进了内分泌命运的指定，包括β细胞谱系，同时耗尽了腺泡命运。两种MSK亚型的胚系敲除导致α细胞的增强和腺泡分化的减少，而Msk1的单等位基因缺失则促进了β细胞的质量。我们的染色质状态动力学屏幕可以应用于其他发育背景，以揭示调节细胞命运的新途径和方法。
Type I diabetes is caused by loss of insulin-secreting beta cells. To identify novel, pharmacologically-targetable histone-modifying proteins that enhance beta cell production from pancreatic progenitors, we performed a screen for histone modifications induced by signal transduction pathways at key pancreatic genes. The screen led us to investigate the temporal dynamics of ser-28 phosphorylated histone H3 (H3S28ph) and its upstream kinases, MSK1 and MSK2 (MSK1/2). H3S28ph and MSK1/2 were enriched at the key endocrine and acinar promoters in E12.5 multipotent pancreatic progenitors. Pharmacological inhibition of MSK1/2 in embryonic pancreatic explants promoted the specification of endocrine fates, including the beta-cell lineage, while depleting acinar fates. Germline knockout of both Msk isoforms caused enhancement of alpha cells and a reduction in acinar differentiation, while monoallelic loss of Msk1 promoted beta cell mass. Our screen of chromatin state dynamics can be applied to other developmental contexts to reveal new pathways and approaches to modulate cell fates.
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影响因子：
10.5
作者：
Iwafuchi-Doi M;Zaret KS
通讯作者：
Zaret KS
影响因子：
3.5
作者：
Arthur, JSC;Cohen, P
通讯作者：
Cohen, P
影响因子：
5.3
作者：
Jacquemin, P;Durviaux, SM;Lemaigre, FP
通讯作者：
Lemaigre, FP
影响因子：
14.9
作者：
Cai W;Wang C;Li Y;Yao C;Shen L;Liu S;Bao X;Schnable PS;Girton J;Johansen J;Johansen KM
通讯作者：
Johansen KM
影响因子：
16
作者：
Goeke, Jonathan;Chan, Yun-Shen;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui